Process of use in converting the 4″(S)-OH functional group of the cladinose unit of an azamacrolide to 4″(R)-NH2

ABSTRACT

The subject-matter of the invention is a process for the stereoselective preparation of a compound of general formula I 
                 
 
by stereoselective displacement by a nitrogenous nucleophilic compound of the activated alcohol functional group present at this 4″ position in a corresponding derivative of formula II.

RELATED APPLICATIONS

This application claims priority from U.S. application Ser. No.60/127,400, filed, Apr. 1, 1999 and from French Application 99 00459,filed Jan. 18, 1999. Reference is also made to U.S. Provisional patentapplication Ser. No. 60/128,383, filed, Apr. 8, 1999 and Frenchapplication 99 03885, filed Mar. 29, 1999. Each of these applications,and each document cited or referenced in each of these applications ishereby incorporated herein by reference. It is hereby stated that theinventive entity of each of U.S. Provisional patent application Ser. No.60/128,383, filed, Apr. 8, 1999, French application 99 03885, filed Mar.29, 1999 and any full U.S. utility application claiming priority fromeither or both of U.S. Provisional patent application Ser. No.60/128,383, filed, Apr. 8, 1999 and French application 99 03885, filedMar. 29, 1999 is not “another” or “others” as to the inventive entity ofthis application, and vice versa. In addition, each document citedherein (“herein cited documents”) and each document referenced or citedin herein cited documents are hereby incorporated by reference.

The subject-matter of the present invention is a process of use inconverting the 4″ (S)-OH functional group of the cladinose unit of anazamacrolide to 4″ (R)—NH2.

The present invention relates more particularly to the field ofmacrolide antibiotics of erythromycin type and more particularly theirazamacrolide derivatives which form the subject-matter of Patent EP508,699 and which correspond to the following general formula:

in which R is a hydrogen atom or a C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl orC₆-C₁₂ arylsulphonyl group, which are, if appropriate, substituted.

These compounds are obtained from erythromycin and their synthesisinvolves two major stages:

-   -   the creation of the 8a-azalide macrocycle starting from the (Z)        oxime, which is subjected to a stereospecific Beckmann        rearrangement, and    -   the modification of the cladinose group at the 4″ position,        which consists of the conversion of the 4″ (S)-OH to 4″ (R)-NH₂,        that is to say with inversion of configuration, which can be        illustrated as follows:

In fact, the route currently used to provide for this conversion of the4″ (S)-OH to 4″ (R)-NH₂ is not completely suitable for production on anindustrial scale.

It involves, successively, an oxidation of the hydroxyl functional groupat the 4″ position to a ketone functional group and then the conversionof this ketone to an oxime, which, by reduction, results in anapproximately 1 to 1 mixture of the expected amino derivative and of its4″ epimer.

This synthetic route consequently has the major disadvantage ofrequiring the formation of sp² C-4″ intermediates and thus of losing thestereochemical information initially present at the sp³ C-4″ of thecladinose unit. This result is all the more of a nuisance since theisomers, acquired on conclusion of this synthetic route, are obtainedwith a low yield of about 20% and are in addition difficult to separate.Thus, for a crude reaction yield of about 20%, only approximately 7% ofthe amino derivative with inversion of configuration is obtained.

The object of the present invention is specifically to provide a newaccess route to these derivatives, aminated at the 4″ position, whichadvantageously makes it possible to retain a significantstereoselectivity and provides a satisfactory yield.

More specifically, a first subject-matter of hi the present invention isa process for the preparation of a compound of general formula I

in which:

-   -   R is a hydrogen atom or a C₁-C₁₀ alkyl, C₂-C₁₀. alkenyl or        C₆-C₁₂ arylsulphonyl group, which are, if appropriate,        substituted, and    -   A, which are identical or different, are        -   a hydrogen atom,        -   a nitrogen atom, if appropriate substituted,        -   a C₁-C₄ alkyl group, which is optionally substituted by one            or more aryl groups, which are, if appropriate, substituted,        -   an R₂CO or R₂SO₂ group, with R₂ being a hydrogen atom, a            C₁-C₁₈ alkyl group or an aryl group, which are, if            appropriate, substituted,    -   ∇ means that the C in the 4″ position has undergone an inversion        of configuration with respect to the formula II, from a compound        of general formula II    -    with:        -   R as defined in general formula I and        -   P₁ being a protective group for the hydroxyl functional            group at the 2′ position, characterized in that it comprises            at least the stages consisting in:    -   activating the hydroxyl functional group at the 4″ position in        the compound of general formula II, in order to obtain a        compound of general formula III    -    in which:        -   R and P₁ are as defined in general formulae I and II and        -   OR₁ is a leaving group,        -   bringing the said compound of general formula III thus            obtained into contact with a nitrogenous nucleophilic            derivative under conditions which are sufficient to allow            the stereoselective displacement of the hydroxyl functional            group activated by the said nitrogenous nucleophile, and        -   deprotecting the hydroxyl functional group at the 2′            position, in order to result in the expected compound of            general formula I.

The claimed process thus has the significant advantage of not requiringthe formation of the sp² C-4″ intermediate necessarily generated in theprior synthetic route discussed above. It involves only an inversion ofconfiguration at the 4″ position and this inversion is obtainedefficiently by displacement by a nitrogenous nucleophile of theactivated alcohol functional group present at this 4″ position.

Consequently, the claimed process proves to be particularly advantageousfor preparing with a very satisfactory yield, a 4″ (R)-NA₂ derivative ofgeneral formula I′

with A and R as defined above from a 4″ (S)-OH azamacrolide derivativeof general formula II′

with R and P₁ as defined above.

As regards the leaving group represented by OR₁ in general formula III,it is preferably selected from C₁-C₂₀ alkyl sulphonates, C₅-C₆ aryl orheteroaryl sulphonates or C₆ to C₂₆ alkylaryl sulphonates, which aresubstituted, if appropriate, by one or more halogen atoms, preferablyfluorine, and/or a nitro, cyano or trifluoromethyl group.

The leaving group represented by OR₁ in general formula III ispreferably a group selected from mesylate, triflate and tosylate and ismore preferably a triflate group.

Use may in particular be made according to the invention, as nitrogenousnucleophilic compound, of compounds of the following types: ammonia,amines which may or may not be substituted by deprotectable groups, suchas a benzyl group or one of its derivatives, amides, imides,sulphonamides, sulphonimides, hydrazines or azides.

According to a preferred alternative form of the claimed process, it ismore preferably an organic organosoluble azide which can be generated insitu.

The leaving groups deriving from the activation of the hydroxylfunctional group at the 4″ position in the general formula II by acompound of formula IVA or IVBBSO₂X or  IVA(BSO₂)₂O  IVBwith:

-   -   X being a halogen atom or a nitrogenous heterocycle, preferably        an imidazole ring, and    -   B being a C₁-C₂₀ alkyl, C₅-C₆ aryl or heteroaryl or C₆-C₂₆        alkylaryl group, which are or are not substituted by one or more        halogen atoms, preferably fluorine, and/or a nitro, cyano or        trifluoromethyl group, are very particularly suitable for the        invention.

The compound of general formula III thus obtained is preferably broughtinto contact with an organosoluble azide in order to result, bystereoselective nucleophilic displacement, in a compound of generalformula V

in which R and P₁ are as defined in general formula I and ∇ means thatthe C in the 4″ position has undergone an inversion of configurationwith respect to the formula II,

The C-4″ carbon of the compound II preferably has a S configuration andthe C-4″ carbon of the compound V a R configuration.

According to this alternative form of the claimed process, a reductionof the said compound of formula V can additionally be carried out, prioror otherwise to the deprotection of the hydroxyl functional group at the2′ position, so as to obtain a compound of general formula I in which Ais a hydrogen atom. This reduction of the azide functional group can becarried out by any conventional method, such as those described by E. F.V. Scriven et al., Chem. Rev. (1988), 88, 297-368. A catalytic reductionwith hydrogen or hydrazine in the presence of palladium-on-charcoal, forexample, or of Raney nickel can in particular be carried out.

On conclusion of this reduction, the expected 4″ (R)-NH₂ aminoderivative, that is to say with inversion of configuration, is thusrecovered with a satisfactory yield.

Consequently, this alternative form of the claimed process is veryparticularly of use in the preparation of the compounds of generalformula I″

in which:

-   -   R is a hydrogen atom or a C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₆-C₁₂        arylsulphonyl group, which are, if appropriate, substituted,        from a compound of general formula II as defined above.

Mention may very particularly be made, as illustration of the azideswhich are suitable for the present invention, of tetra(C₁ to C₂₀alkyl)ammonium or -phosphonium azide, substituted or unsubstitutedtriarylsulphoniums and hexa(C₁ to C₂₀ alkyl)guanidiniums.

According to a preferred alternative form of the invention, it is atetraalkylammonium azide and more particularly tetrabutyl- ortetraoctylammonium azide.

In a specific embodiment of the invention, the azide derivative isformed in a two-phase medium and more specifically in solid/liquid phasetransfer. In this case, the organosoluble azide is generated in situfrom an inorganic azide, such as sodium azide, and from a phase transferagent in the presence of the compound of general formula III in anorganic solvent. The phase transfer agent is preferably a tetra(C₁ toC₂₀ alkyl)ammonium or -phosphonium methanesulphonate.

As regards the compound of general formula II, it is generally obtainedbeforehand by protection of the hydroxyl functional group at the 2′position in the corresponding derivative. Of course, this protection iscarried out conventionally using a conventional protective group for thehydroxyl functional group, such as those which appear in “ProtectiveGroups in Organic Synthesis”, Second Edition, Theodora W. Greene and P.G. Wuts, Wiley Intersciences, p. 10-142. The procedures for carrying outthe protecting and deprotecting operations are also described in thework referred to above.

Following this protection of the hydroxyl functional group at the 2′position, the hydroxyl functional group at the 4″ position is activated.This activation of the compound of general formula II is also carriedout under conventional operating conditions, such as those described in“Protective Groups in Organic Synthesis”, Second Edition, Theodora W.Greene and P. G. M. Wuts, Wiley Intersciences, p. 117-118. The examplessubmitted below describe a detailed procedure for the activation of the4″ hydroxyl functional group with triflic anhydride.

As regards the nucleophilic substitution reaction, it is carried out inan organic solvent, preferably an anhydrous organic solvent. In thepreferred alternative form of the invention employing an organosolubleazide, aromatic solvents, such as benzene and toluene, or ethers, suchas THF or methyl tert-butyl ether, are suitable in particular assolvents.

The nitrogenous nucleophilic compound, preferably the azide, is used ina proportion of approximately 1 to 30 equivalents with respect to thecompound of formula III and preferably in a proportion of approximately1 to 5 equivalents.

The temperature is conventionally between −20 and 180° C. As a generalrule, it is adjusted so as to favour the kinetics of the reactionwithout harming the stability of the compounds.

According to a preferred alternative form of the invention, in the firststage, the hydroxyl functional group at the 4″ position is activated bya trifluoromethanesulphonate group and the nucleophilic substitution iscarried out with inversion of configuration with tetrabutyl- ortetraoctylammonium azide in toluene at room temperature.

According to a preferred alternative form of the invention, R is amethyl group in the general formula I, I′, II′, II″, III and V and A ahydrogen atom in the general formula I and I′.

Another subject-matter of the present invention is the compounds ofgeneral formula VI

in which

-   -   P₂ is a hydrogen atom or a protective group,    -   R is a hydrogen atom or a C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₆-C₁₂        arylsulphonyl group, which are, if appropriate, substituted, and    -   OR₁ is a leaving group, as intermediates in the preparation of a        compound of general formula I.

More preferably, R is a methyl group and OR₁ is a triflate group andmore preferably the C-4″ carbon has a R configuration.

The present invention also relates to the compounds of general formulaVII

in which

-   -   P₂ is a hydrogen atom or a protective group,    -   R is a hydrogen atom or a C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₆-C₁₂        arylsulphonyl group, which are, if appropriate, substituted, and    -   A, which are identical or different, are        -   a nitrogen atom, if appropriate substituted,        -   a C₁-C₄ alkyl group, which is optionally substituted by one            or more aryl groups, which are, if appropriate, substituted,    -   as intermediates in the preparation of a compound of general        formula I.

More preferably, R is a methyl group and NA₂ an N₃ group and morepreferably, the C-4″ carbon has a R configuration.

The examples which appear below are presented by way of illustration andwithout implied limitation of the present invention.

EXAMPLE 1 Preparation of the compound 4″-dehydroxy-4″(R)-amino-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A:

The synthetic scheme used is as follows:

All the tests are carried out under an inert atmosphere.

1) Formation of 4″(S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycinA:

Pyridine (39.5 mg, 0.51 mmol, 5 equiv.) is added to a solution ofalcohol 2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A (0.1g, 0.12 mmol, 1 equiv.) in anhydrous dichloromethane (0.4 ml). Thesolution is cooled to 0° C. and then a solution of triflic anhydride(42.3 mg, 0.15 mmol, 1.2 equiv.) is added dropwise. The solution isstirred for 1 h at 0° C. and then 30 min at room temperature. Afterdiluting the reaction mixture with anhydrous dichloromethane (10 ml),the reaction mixture is cooled to 0° C. and then hydrolysed by additionof a saturated aqueous sodium bicarbonate solution (10 ml). The organicphase is separated and then washed with distilled water (10 ml), driedover magnesium sulphate and evaporated. The crude product is taken up inheptane (10 ml) in order to remove any trace of residual pyridine byazeotropic distillation. 110.4 mg of 4″(S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homo-erythromycinA are obtained with a purity greater of than or equal to 90%. Thestructure is confirmed by NMR and MS analysis.

2) Formation of 4″-dehydroxy-4″(R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A:

A 0.58M solution of tetrabutylammonium azide in toluene (4.5 ml; app.1.3 equiv.) is added to unpurified 4″(S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycinA from the preceding stage (1.84 g, 2.0 mmol, 1 equiv.) at roomtemperature. The reaction mixture is stirred for 3 days at roomtemperature and then diluted with toluene (25 ml). This solution iswashed three times with distilled water (3×10 ml), then dried overmagnesium sulphate and evaporated. 1.63 g of4″-dehydroxy-4″(R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homo-erythromycinA are obtained with a purity of 70%. The structure is confirmed by NMRand MS analysis.

3) Formation of the compound 4″-dehydroxy-4″(R)-amino-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A:

Raney nickel (200 mg) is added to a solution in isopropanol (5 ml) ofunpurified4″-dehydroxy-4″(R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homo-erythromycinA from the preceding stage (250.0 mg, 0.30 mmol, 1 equiv.). Hydrazinemonohydrate (30 microliters, 0.6 mmol, 2 equiv.) is added every 30minutes. The reaction time is 2 h. The reaction mixture is diluted withethyl acetate (10 ml) and filtered. The filtrate is washed with asaturated aqueous sodium bicarbonate solution (10 ml) and then withwater (10 ml). After drying over magnesium sulphate, the filtrate isevaporated. 230 mg of 4″-dehydroxy-4″(R)-amino-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A areobtained with a purity of 60%. The structure is confirmed by NMR and MSanalysis.

EXAMPLE 2

Tetraoctylammonium azide (190.3 ml, 0.5 mmol, 5 equiv.) is added at roomtemperature to a solution of 4″(S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycinA (92.3 mg, 0.1 mmol, 1 equiv.) in toluene (0.2 ml). After stirring fortwo days at room temperature, tetraoctylammonium azide (58 mg, 0.15mmol, 1.5 equiv.) is again added. After stirring for an additional twodays at room temperature, the reaction mixture is diluted with toluene(10 ml) and washed with water (10 ml). The organic phase is separatedand dried over sodium sulphate. After evaporating the solvents, ¹H NMRanalysis shows the predominant presence of the compound 4″-dehydroxy-4″(R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A.

EXAMPLE 3

Tetrabutylphosphonium methanesulphonate (355 mg, 1 mmol, 5 equiv.) andthen sodium azide (325 mg, 5 mmol, 25 equiv.) are successively added toa solution of 4″(S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycinA (185 mg, 0.2 mmol, 1 equiv.) in toluene (0.4 ml) at room temperature.After stirring for three days at room temperature, the reaction mixtureis diluted with toluene (10 ml) and washed with water (10 ml). Theorganic phase is separated and dried over sodium sulphate. Afterevaporating the solvents, ¹H NMR analysis shows the predominant presenceof the compound 4″-dehydroxy-4″(R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A.

EXAMPLE 4

Tetraoctylammonium methanesulphonate (217 mg, 0.38 mmol, 3.8 equiv.) andthen tetrabutylammonium azide (158 mg, 2.5 mmol, 25 equiv.) aresuccessively added to a solution of 4″(S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycinA (92 mg, 0.1 mmol, 1 equiv.) in toluene (0.25 ml) at room temperature.After reacting for 4 days at room temperature, the reaction mixture isdiluted with toluene (10 ml) and washed with water (10 ml). The organicphase is separated and dried over sodium sulphate. After evaporating thesolvents, ¹ H NMR analysis shows the predominant presence of thecompound 4″-dehydroxy-4″(R)-azido-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A.

EXAMPLE 5

A solution of 4″(S)-trifluoromethylsulphonyl-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycinA (21.4 mg, 0.023 mmol) in N-methylpyrrolidinone is saturated withgaseous ammonia. This solution is stirred for 48 h at room temperature.The reaction mixture is subsequently diluted with ethyl acetate (10 ml)and washed with water (15 ml). The organic, phase is separated, driedover sodium sulphate and evaporated. LC/MS analysis shows the formationof 22%, by internal standardization, of 4″-dehydroxy-4″(R)-amino-2′-acetoxy-9-deoxo-8a-aza-8a-methyl-8a-homoerythromycin A.

1. A process for the stereoselective preparation of a compound offormula I

 wherein: R is a hydrogen atom or a C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl orC₆-C₁₂ arylsulphonyl group, optionally substituted; A, each of which isidentical or different, is a hydrogen atom, a nitrogen atom, optionallysubstituted, a C₁-C₄ alkyl group, which is optionally substituted by oneor more aryl groups, which are, in turn, optionally substituted, an R₂COor R₂SO₂ group, with R₂ being a hydrogen atom, a C₁-C₈ alkyl group or anaryl group, which are, optionally substituted; and ∇ indicates that theC in the 4″ position has undergone an inversion of configuration withrespect to the formula II, from a compound of formula II:

 wherein: R as defined in formula I and P₁ is a protective group for thehydroxyl functional group at the 2′ position, comprising the steps of:(i) activating the hydroxyl functional group at the 4″ position in thecompound of formula II, in order to obtain a compound of formula III:

 wherein: R and P₁ are as defined in formulae I and II and OR₁ is aleaving group; (ii) contacting the compound of formula III with anitrogenous nucleophilic derivative under conditions which aresufficient to allow the stereoselective displacement of the hydroxylfunctional group activated by the said nitrogenous nucleophile; and(iii) deprotecting the hydroxyl functional group at the 2′ position. 2.The process according to claim 1, wherein a 4″-(R)—NA₂ of formula I′:

wherein A and R are as defined in claim 1, is prepared from a 4″-(S)—OHderivative of formula II′:

wherein R and P₁ are as defined in claim
 1. 3. The process according toclaim 1, wherein the leaving group represented by OR₁ in formula III isselected from the group consisting of C₁-C₂₀ alkyl sulphonates, C₅-C₆aryl sulphonates, C₅-C₆ heteroaryl sulphonates and C₆-C₂₆ alkylarylsulphonates, which are optionally substituted by one or more halogenatoms and/or a nitro, cyano or trifluoromethyl group.
 4. The processaccording to claim 1, wherein the leaving group represented by OR₁ informula III is a triflate group.
 5. The process according to claim 1,wherein the leaving group derives from the activation of the hydroxylfunctional group at the 4″ position in the formula II by a compound offormula IVA or IVB:BSO₂X or (BSO₂)₂O  IVA or IVB wherein: X is a halogen atom or anitrogenous heterocycle; and B is a C₁-C₂₀ alkyl, C₅-C₆ aryl orheteroaryl, or C₆-C₂₆ alkylaryl group, which is optionally substitutedby one or more halogen atoms and/or a nitro, cyano or trifluoromethylgroup.
 6. The process according to claim 1, wherein the nitrogenousnucleophilic compound is selected from the group consisting of ammoniaand amines, optionally substituted by deprotectable groups, amides,imides, sulphonamides, sulphonimides, hydrazines or azides.
 7. Theprocess according to claim 1, wherein the nitrogenous nucleophiliccompound is used in a proportion of approximately 1 to 30 equivalentswith respect to the compound of formula III.
 8. The process to claim 1,wherein the nitrogenous nucleophilic compound is an organicorganosoluble azide, optionally generated in situ.
 9. The processaccording to claim 1, further comprising: activating the compound offormula II with a compound of formula IVA or IVBBSO₂X or   IVA(BSO₂)₂O   IVB  wherein: X is a halogen atom or a nitrogenousheterocycle; and B is a C₁-C₂₀ alkyl, C₅-C₆ aryl or heteroaryl or C₆-C₂₆alkylaryl group, which are optionally substituted by one or more halogenatoms and/or a nitro, cyano or trifluoromethyl group; and contacting thecompound of formula III with an organic organosoluble azide in order toresult, by stereoselective nucleophilic displacement, in a compound offormula V

wherein R and P₁ are as defined in formula I and ∇ indicates that the Cin the 4″ position has undergone an inversion of configuration withrespect to the formula II.
 10. The process according to claim 1, furthercomprising: activating the compound of formula II with a compound offormula IVA or IVBBSO₂X or   IVA(BSO₂)₂O   IVB  wherein: X is a halogen atom or a nitrogenousheterocycle, and B is a C₁-C₂₀ alkyl, C₅-C₆ aryl or heteroaryl or C₆-C₂₆alkylaryl group, optionally substituted by one or more halogen atomsand/or a nitro, cyano or trifluoromethyl group; contacting the compoundof formula III with an organic organosoluble azide resulting, bystereoselective nucleophilic displacement, in a compound of formula V:

 wherein: R and P₁ are as defined in formula I and ∇ means that the C inthe 4″ position has undergone an inversion of configuration with respectto the formula II; and reducing the compound of formula V, so as toobtain a compound of formula I in which A is a hydrogen atom.
 11. Theprocess according to claim 1, further comprising: activating thecompound of formula II with the C-4″ carbon having S configuration witha compound of formula IVA or IVBBSO₂X or   IVA(BSO₂)₂O   IVB  wherein: X is a halogen atom or a nitrogenousheterocycle, and B is a C₁-C₂₀ alkyl, C₅-C₆ aryl or heteroaryl or C₆-C₂₆alkylaryl group, optionally substituted by one or more halogen atomsand/or a nitro, cyano or trifluoromethyl group; contacting the compoundof formula III with an organic organosoluble azide in order to result,by stereoselective nucleophilic displacement, in a compound of formula V

wherein R and P₁ are as defined in formula I, the C-4″ carbon has a Rconfiguration and ∇ indicates that the C in the 4″ position hasundergone an inversion of configuration with respect to the formula II.12. The process according to claim 1, wherein the nitrogenousnucleophilic compound is an organic organosoluble azide selected fromthe group consisting of tetra-(C₁ to C₂₀ alkyl) ammonium azide,tetra-(C₁ to C₂₀ alkyl) phosphonium azide, substituted or unsubstitutedtriarylsulphoniums and hexa (C₁ to C₂₀ alkyl)-guanidiniums.
 13. Theprocess according to claim 1, wherein the nitrogenous nucleophiliccompound is a tetrabutylammonium azide or tetraoctylammonium azide. 14.The process according to claim 1, wherein the nitrogenous nucleophiliccompound is an organic organosoluble azide and the nucleophilicdisplacement of the leaving group at the 4″ position by the organicorganosoluble azide is carried out in a solvent selected from the groupconsisting of aromatic solvents and ethers.
 15. The process according toclaim 1, wherein, in the first stage, the hydroxyl functional group atthe 4″ position is activated by a trifluoromethanesulphonate group andthe nucleophilic substitution is carried out with inversion ofconfiguration with tetrabutyl-ortetraoctylammonium azide in toluene atroom temperature.
 16. The process according to claim 1, wherein R is amethyl group in the formula I, I′, II, II′, III and V and A a hydrogenatom in the formula I and I′.
 17. A compound of formula VI

wherein: P₂ is a hydrogen atom or a protective group; R is a hydrogenatom or a C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₆-C₁₂ arylsulphonyl group,optionally substituted; and OR₁ is a leaving group.
 18. The compound offormula VI according to claim 17, wherein R is a methyl group and OR₁ isa triflate group.
 19. The compound of formula VI according to claim 18,wherein the C-4″ carbon has a S configuration.
 20. A compound of formulaVII

wherein: P₂ is a hydrogen atom or a protective group; R is a hydrogenatom or a C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl or C₆-C₁₂ arylsulphonyl group,optionally substituted; and A, each of which is identical or different,is a nitrogen atom, optionally substituted, or a C₁-C₄ alkyl group,which is optionally substituted by one or more aryl groups, which are,in turn, optionally substituted, wherein A is not a hydrogen atom or aR₂CO or R₂SO₂ group, with R₂ being a hydrogen atom, a C₁-C₈ alkyl groupor an aryl group, which are, optionally substituted.
 21. The compound offormula VII according to claim 20, wherein R is a methyl group and N(A)₂is a N₃ group.
 22. The compound of formula VI according to claim 20,wherein the C-4″ carbon has a R configuration.
 23. The process accordingto claim 3, wherein the halogen atom is fluorine.
 24. The processaccording to claim 5, wherein the nitrogenous heterocycle is animidazole ring.
 25. The process according to claim 5, wherein thehalogen atom is fluorine.
 26. The process according to claim 9, whereinthe nitrogenous heterocycle is an imidazole.
 27. The process accordingto claim 10, wherein the nitrogenous heterocycle is an imidazole. 28.The process according to claim 10, wherein the halogen atom is fluorine.29. The process according to claim 11, wherein the nitrogenousheterocycle is an imidazole.
 30. The process according to claim 11,wherein the halogen atom is fluorine.
 31. The process according to claim14, wherein the ether is selected from the group consisting of methyltert-butyl ether and THF.
 32. The process according to claim 14, whereinthe solvent is selected from the group consisting of benzene andtoluene.